B. Konig, P. Bubenitschek, P. G. Jones 195

Synthesis of Fluorenylidene- and 9-Alkylidene-3,6-dimethyl-4,5-diazafluorene Compounds from 2,2’-Biarene-3,3’-diyl Bis(triflate) by a Palladium-Catalyzed Domino Process Burkhard Konig*”, Peter Bubenitscheka, and Peter G. Jonesb

Institut fur Organische Chemie der Technischen Universitat Braunschweig”, Hagenring 30, D-38106 Braunschweig, Germany

Institut fur Anorganische und Analytische Chemie der Technischen Universitat Braunschweigb, Hagenring 30, D-38 106 Braunschweig, Germany

Received August 6, 1994

Key Words: Cyclization, palladium-catalyzed I Fluorenylidene, 4,5-diazafluorenylidene I Ozonolysis

A convenient synthesis of the fluorenylidene and the 4,5-di- azafluorenylidene moiety is described. The palladium-cata- lyzed coupling of 6,6’-dimethyl-2,2’-bipyrdine-3,3‘-diyl bis- (triflate) (2) with phenylacetylene leads to the 4,5-diazafluo- renylidene compound 4 as the major reaction product by an

intramolecular cyclization. Under the same conditions bi- phenyl-2,2‘-diyl bis(triflate) (6) gives the threefold coupling product ?. The connectivity of 4 and ? is confirmed by crystal structure analysis.

Nitrogen analogs of fluorenes and fluorenones are an interesting class of compounds, and much attention has been paid to them by synthetic and medicinal chemists because of their potential biologi- cal properties[’]. The ability of 4,5-diazafluoren-9-one to chelate metal ions has been used to design DNA binding complexes with nuclease activityL21, whereas the molecular geometry of the 4,5-di- azafluorene substructure is responsible for the selectivity of syn- thetic receptors in the oriented binding of uric acid-type mol- ecule~[~]. Most synthetic routes to 4,5-diazafluorene derivatives have employed 4,5-diazafluoren-9-one (5-H)I41 as a starting mater- ial. However, the only described synthesis of 5-H is the oxidative cleavage of 1,lO-phenanthroline by alkaline potassium permanga- nate in low yield[4].

In this paper, we report on a new and efficient synthetic route to a substituted diazafluorenylidene derivative and its conversion to 3,6-dimethyl-4,5-diazafluoren-9-one (5-Me). 6,6’-Dimethyl-2,2‘-bipyridine-3,3’-diol (1) is readily obtained

from the commercially available 3-hydroxy-6-methylpyridine ac- cording to a literature Compound 1 is converted to the triflic diester 2r61 in high yield by treatment with triflic anhy- dride in dichloromethane at room temperature. The palladium-cat- alyzed reaction of 2 with phenylacetylene in DMF and NEt3 at 60°C gives two products with identical molecular mass in 64 and 12% isolated yield. The minor product is identified as the expected twofold coupling product 3, while the NMR spectra of the major compound clearly indicate an unsymmetrical structure. The struc- ture is determined by X-ray which confirms that an in- tramolecular cyclization to 4 has taken place.

A mechanistic rationale is given in Scheme 3. The initial coupling product of phenylacetylene with one triflic ester leads to the inter- mediate 8, traces of which can be isolated from the reaction mix- ture. Palladium insertion into the remaining triflate-carbon bond is followed by cis addition to the triple bond[s]. The reaction se- quence is terminated by the coupling of a second phenylacetylene

molecule with the vinylpalladium species 10 to give 4. The ratio of 3 and 4 is not changed by a tenfold excess of phenylacetylene or the use of the more reactive tributyltin derivative.

Figure 1 shows the crystal structure of 4L71, conforming the pro- posed connectivity. The central fluorenylidene moiety is nearly planar within a deviation of only 0.065 pm. The close proximity of the proton at C-8 to the phenyl ring at C-10 is reflected by its downfield shift to 6 = 8.92 in the ‘H-NMR spectra.

The central double bond of 4 is cleaved by treating a dichloro- methane solution with ozone at -78°C. Subsequent reductive workup with PPh3 gives 3,6-dimethyl-4,5-diazafluoren-9-one (5- Me) in 80% yield as yellow crystals.

When the carbocyclic analog 6l61 is allowed to react with phenyl- acetylene under the same conditions the yne-diene 7 is obtained. The structure is again determined by X-ray crystallography (Figure 2), showing that the addition of a third phenylacetylene unit has taken place[7]. The acyclic twofold coupling product can only be detected in traces.

A likely pathway for the product formation consists of the cis addition of phenylacetylene to the intermediate 10 yielding 11. The sequence is terminated by the coupling of phenylacetylene with this vinylpalladium species giving 7. The formation of different prod- ucts with carbocyclic and heterocyclic substrates can be explained by the modified reactivity of the palladium catalyst due to coordi- nation with 2,2-bip~ridine[~I.

The described reaction sequence provides a simple entry to 4 5 diazafluorene derivatives utilizing the readily obtainable bipyridine 1. With an overall yield of 52% for the cyclization and ozonolysis step, the procedure may be an economical alternative to the pre- viously described oxidative cleavage of 1,lO-phenanthroline for the synthesis of bidentate metal ligands and synthetic receptors of the 4,Sdiazafluorene type. The formation of 7 is an example of a pal- ladium-mediated four-step domino reaction.

Liebigs Ann. 1995,195- 198 0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1995 0947-3440/95/0101-0195 $10.00+.25/0

196 B. Konig, P. Bubenitschek, P. G. Jones

Scheme 1. a: (CF3S02)20, CH2C12, room temp., 6 h; yield 85%. - b: phenylacetylene, PdC12(PPh3)2 ( 5 mol-Yo), DMF, 60°C, 12 h; yield 12% of 3 and 65% of 4. - c: 1) CH2CI2, 03, -78°C; 2) PPh3; yield 80%

Ekheme 2. b: PhenYlacetYleW pdc12(pph3)2 (5 mol-%), DMF, 60°C; yield 42%

3

C 4 -

b OSOzCF3 /

CF3S02d

b

\ / \ /

6 7

Scheme 3. Reaction pathways for the formation of 4 and 7. - I: X = N, R = CH3; 11: X = CH, R = H

& [Pd] Pd-OS02CF3 - \ I \ / ' / R CF3S020 R

4 8 9

5-H : R = H 5-Me: R = C H 3

B. K. thanks the Fonds der Chemischen Industrie for a Liebig stipend and Prof. Dr. H. Hopffor his support. Generous gifts of chemicals from the Degussa AG and grants from the Fonds der Chemischen Industrie, Deutsche Forschungsgemeinschaft and the Volkswagen-Stifttung are gratefully acknowledged.

10

Experimental 'H NMR: Bruker AM 400; 6 = 0 for tetramethylsilane as in-

ternal standard, 6 = 7.26 for chloroform. - 13C NMR: AM 400; 6 = 77.0 for deuteriochloroform; the multiplicity of the I3C-NMR signals was determined by the DEPT technique and quoted as (+) for CH3 and CH groups, for CH2 and (Cquat) for quaternary carbon atoms. - IR: Nicolet 320 FT-IR. - MS: Finnigan MAT 8430. - UVNis: Hewlett Packard 8452A. - Melting points: not corrected, hot-plane microscope apparatus. - Column chromatog- raphy (CC): Merck silica gel 60, mesh 70-230; PE (60170) means

petroleum ether with a boiling range of 60-70°C. - TLC: silica

X-Ray Structure Determination of Comp0und4[~]: C28H20N2 . 0.5 C7H8 (430.53), triclinic, space group Pi, a = 852.2(2), b = 992.9(3), c = 1497.6(4) pm, a = 71.29(2), p = 83.09(2), y = 77.59(2)", V =

(Macherey-Nagel; sil G'uv254).

Liebigs Ann. 1995, 195-198

Fluorenylidene- and 9-Alkylidene-3,6-dimethyl-4,5-diazafluorene Compounds 197

Figure 1. Structure of 4 in the crystal; selected bond lengths [pm] and angles ["I: C(9)-C(10) 135.9(4), C(la)-C(4a) 139.9(4), C(4a)-C(5a) 146.5(4), C(Sa)-C(8a) 140.4(4), C(ll)-C(12) 120.2(4); C( lO)-C(9)-C( la) 126.7(2), C(9)-C( 10)-C( 11) 120.2(3)

%C20 P

Q

0.7879(6) nm3, Z = 2, h(Mo-K,) = 0.71073 A, p = 0.071 mm-I, D, = 1.222 Mg m-,, F(000) = 328, T = 143 K. A pale yellow prism with the dimensions 0.6 X 0.25 x 0.15 mm was mounted on a glass fiber in inert oil and transferred to the cold gas stream of a Stoe STADI-4 diffractometer with a Siemens LT-2 low-temperature attachment. Cell constants were refined from +o values of 52 re- flections in the 2 0 range 20-23". A total of 4354 intensities (4103 unique, Rint = 0.0257) were measured to 2 0 50". The structure was solved by direct methods and refined anisotropically on P (pro- gram SHELXL-93, G. M. Sheldrick, University of Gottingen). Hy- drogen atoms were included with a riding model. The toluene mol- ecule is disordered over an inversion center. The final w R ( P ) for all reflections was 0.106, with a conventional R(F) of 0.062, for 337 parameters.

X-Ray Structure Determination of Compound 7"l: C36H24 (456.55), monoclinic, space group P2Jn, u = 1085.61(12), b = 577.32(8), c = 3859.5(5) pm, = 95.641(10)", V = 2.4072(5) nm3, Z = 4, h(Mo-K,) = 0.71073 A, p = 0.071 mm-I, D, = 1.260 Mg m-,, F(OO0) = 960, T = 173 K. A yellow prism with the dimen- sions 1.00 X 0.34 X 0.28 mm was mounted as above. Measure- ments were performed on a Siemens P4 diffractometer with low- temperature attachment. Cell constants were refined from setting angles of 62 reflections up to 2 0 25". A total of 6710 intensities (4231 unique, R,,, = 0.0179) were measured to 2 0 50". The struc- ture was solved and refined as above. The final w R ( p ) for all reflec- tions was 0.1 12, with a conventional R(F) of 0.068, for 325 para- meters.

6,6'-Dimethyl-2,2'-bipyuidine-3,3'-diyl Bis(trijluoromethanesu1- fonate) (2): To a solution of 1.0 g (4.6 mmol) of 1 in 50 ml of dry dichloromethane were added at 0°C 1.7 ml (10.4 mmol) of (CF3S02)0 and 1.5 ml(l1 .O mmol) of NEt3. The reaction mixture was stirred at room temp. for 6 h and poured into 100 ml of water. The organic phase was washed with 50 ml of water, dried with MgS04 and concentrated in vacuo to yield 1.85 g (83%) of 2 as a slowly solidifying yellow oil. A small analytical sample was crys- tallized from CH2C12/PE. - IR (neat): 3 = 1584 cm-I, 1426, 1210,

Figure 2. Structure of 7; selected bond lengths Lpm] and angles ["I: C(9)-C(lO) 137.4(2), C(19)-C(11) 145.2(2), C(Il)-C(12) 135.8(2), C( 12)- C( 13) 143.4(2), C( 13)- C( 14) 120.0(2); C(9)-C(IO)-C( 11) 122.1(2), C(12)-C(l l)-C(lO) 129.2(2),

C( 1 1)-C( 12)-C( 13) 125.1(2), C( 14)-C( 13)-C( 12) 170.9(2)

0

a 3 0

1136, 876. - UV (CH,CN): h,, (lg E) = 192 nm (4.602), 230 (3.971), 278 (3.965). - 'H NMR (400 MHz, CDC13): 6 = 2.64 (s, 6H), 7.33 (d, 7.4 Hz, 2H), 7.63 (d, 3J= 7.5 Hz, 2H). - I3C NMR (100 MHz, CDCI,): 6 = 23.58 (+), 118.26 (q, lJC.F = 320.3

158.56 (Cquat). - MS (70 eV), mlz ("h): 480 (60) [M+], 214 (100).

C 35.34, H 1.94, N 5.70. - Mol. mass 480 (MS).

9- (I, 3-Diphenyl-2-propynylidene) -3,6-dirnethyl-4,5-diazajluorene (4): 440 mg (0.92 mmol) of 2, 205 mg (2.0 mmol, 220 pl) of phenyl- acetylene, 1.7 ml (12.3 mmol) of NEt3, and 28 mg (4.4 mol-Yo) of Pd(PPh3)2C12 in 15 ml of DMF were allowed to react at 60°C under nitrogen for 12 h. The reaction mixture was diluted with 100 ml of ethyl acetate, washed with water (8 X 50 ml), the organic phase dried with MgS04 and concentrated in vacuo. The crude product was chromatographed on silica gel to yield three fractions. - Frac- tion I (PE/ethyl acetate, 2: 1): phenylacetylene, not isolated, RF = 0.9. - Fraction I1 (PE/ethyl acetate, 1 :3): 225 mg (65%) of 4, Rf = 0.75, as a yellow solid, m.p. 184°C. - IR (KBr): 3 = 3027 cm-I, 2184, 1573, 1409. - UV (CH,CN): A,,, (lg E) = 194 nm (4.792),

Hz, CF3), 125.23 (+), 130.44 (+), 143.18 (Cquat), 145.96 (Cquat),

- C L ~ H ~ O F ~ N Z O ~ S ~ (480.4): calcd. C 35.01, H 2.10, N 5.83; found

238 (4.660), 326 (4.397), 368 (4.443), 406 (3.490). - 'H NMR (400 MHz, CDCI3): 6 = 2.62 (s, 3H), 2.74 (s, 3H), 6.65 (d, ' J = 8.1 Hz, lH), 6.74 (d, ,J= 8.1 Hz, lH), 7.20 (d, ,J= 8.1 Hz, lH), 7.36 (m, 3H), 7.50 (m, 7H), 8.92 (d, , J = 8.1 Hz, 1H). - I3C NMR

(Cquat), 122.02 (+), 122.63 (+), 124.81 (Cquat), 128.57 (+), 128.84 (+), 128.95 (+), 128.97 (+), 129.21 (+), 129.81 (Cquat), 130.51 (CqUat), 131.60 (+), 131.80 (+), 132.14 (+), 134.69 (Cquat), 138.83

- MS (70 eV), m/z (YO): 384 (100) [M+]. - CzsHloNz (384.5): calcd. C 87.47, H 5.24, N 7.29; found C 87.56, H 5.30, N 7.00. Mol. mass 384 (MS). - Fraction I11 (PElethyl acetate, 1:3): 41 mg (12%) of

(100 MHz, CDC13): 6 = 24.49 (+), 24.68 (+), 91.05 (Cquat), 102.56

(Cquat), 157.05 (Cquat), 157.21 (Cquat), 159.43 (Cquat), 159.71 (Cquat).

Liebigs Ann. 1995, 195- 198

198 B. Konig, P. Bubenitschek, P. G. Jones

6,6‘-dimethyl-3,3‘-bis(phenylethynyl)-2,2‘-bipyridine (3), Rf = 0.4, m.p. 175°C. - IR (KBr): 5 = 3060 cm-I, 2248, 1582, 1248. - UV (CH3CN): I,,, (lg E ) = 192 nm (4.654), 224 (4.295), 288 (4.444),

(s, 6H), 7.21 (d, 3 J = 8.1 Hz, 2H), 7.23 (m, lOH), 7.84 (d, 3 J =

(Cquat), 94.80 (C,,,), 116.87 (C,,,), 122.53 (+), 123.21 (+), 128.23 (+), 128.28 (C,,,), 131.39 (+), 139.66 (+), 157.57 (Cquat), 158.66 (Cquat). - MS (70 eV), mlz (YO): 384 (100) [M+]. - C2&& (384.5): calcd. C 87.47, H 5.24, N 7.29; found C 87.21, H 5.21, N 7.35. - Mol. mass 384 (MS).

306 (4.375), 326 (3.451). - ’H NMR (400 MHz, CDC13): 6 = 2.65

8.0 Hz, 2H). - I3C NMR (100 MHz, CDC13): 6 = 24.75 (+), 86.45

3,6-Dimethyl-4,.5-diazaJ7uoren-9-one (5): Ozone was introduced into a solution of 384 mg (1.0 mmol) of 4 in 60 ml of CH2C12 at -78°C for 1 h. Nitrogen was bubbled through the solution to re- move the excess ozone, 786 mg (3.0 mmol) of PPh3 was added, and the reaction mixture was allowed to warm up to room temp. over 1 h. The solvent was removed in vacuo, and the solid residue was chromatographed on silica gel (PElethyl acetate, 1 :2) to yield 166 mg (80%) of 5, (Rf = 0.35), as a yellow solid, m.p. 145°C. - IR (KBr): F = 3055 cm-I, 2923, 1709, 1600, 1567. - UV (CH3CN): h,,, (Ig E) = 196 nm (4.339), 246 (4.609), 312 (3.889), 326 (3.968), 340 (3.200). - ‘H NMR (400 MHz, CDC13): 6 = 2.69 (s, 6H), 7.12 (d, 3 J = 7.6 Hz, 2H), 3.30 (d, 3 J = 7.6 Hz). - I3C NMR (100 MHz, CDC13): 6 = 25.05 (+), 124.01 (+), 127.28 (Cquat), 131.44 (+), 163.44 (Cquat), 165.49 (C,,,), 189.44 (Cquat). - MS (70 eV), mlz (“h): 210 (100) [M+]. - CI3Hl0N20 (210.2): calcd. C 74.27, H 4.79, N 13.32; found C 74.49, H 4.70, N 13.01. - Mol. mass 210 (MS).

9-(1,3,.5- Triphenyl-2-penten-4-ynylidene)-9H-J7uorene (7): 450 mg (1.0 mmol) of 6L61, 260 mg (2.5 mmol) of phenylacetylene, 1.8 ml (13 mmol) of NEt3, and 35 mg (5 mol-%) of PdC12(PPh3)2 were heated in 15 ml of DMF under N2 for 12 h. The reaction mixture was diluted with 100 ml of dichloromethane, washed with water (5 X 50 ml), the organic phase was dried with MgS04 and sub-

sequently concentrated in vacuo. The solid residue was chromato- graphed on silica gel (PEldichloromethane, 5:l) to yield 191 mg (42%) of 7 (Rf = 0.3), m.p. 182°C. - IR (KBr): 0 = 3045 m-I, 2938, 1600. - UV (CH3CN): h,,, (lg E ) = 192 nm (4.793), 224 (4.418), 286 (4.137), 312 (4.087), 404 (3.791). - ‘H NMR (200 MHz, CDC13): 6 = 6.50 (m, lH), 6.95 (m, IH), 7.30-7.85 (m, 21 H), 8.90 (m, 1 H). - MS (70 eV), mlz (YO): 456 (6) [M+], 450 (80), 184 (100). - C36H24 (456.6): calcd. C 94.70, H 5.30; found C 94.50, H 5.52. - Mol. mass 456 (MS).

[la] J. H. Jensen, T. D. Costello, L. De Brabander, Jr., M. E. Voss, U. S. Patent 5272269, 1993; Chem. Abstr. 1993, 120, 217647~. - [Ib] W. W. Wilkerson, Ch. A. Telaha, World Patent 9314092,1993, Chem. Abstr. 1993,119,249937n. - [Ic] K. Kloc, J. Mlochowski, S. Zdzislaw, L Prakt. Chem. 1977, 319,

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1’1 Full crystallographic details for 4 and 7 are available on request from the Fachinformationszentrum Karlsruhe, D-76344 Eggen- stein-Leopoldshafen, Germany, referring to No. CSD-40 1 262 (4) or -401 263 (7) and the full literature citation.

L8] For a recent examule of a similar cvclization orocess vieldine a

959-967.

six-membered ring see: J. Barry, T. Kodadek, ‘Tetrahehron Lett.

c91 [9a1 J. L. Burmesiter, F. Basolo, Znorg. Chem. 1964, 3, 1587-1593. - [9b1 P. C. Chich, J . Chem. Soc., Dalton Trans.

1994, 3.5, 2465-2468.

1972. 1643-1646. [324/94]

Liebigs Ann. 1995, 195- 198